Cancer is one of the major causes of death. Cancer exceeds heart and cerebrovascular diseases in causing death. Accordingly, many studies have been conducted with enormous expense and time to overcome cancer. However, despite a variety of therapies such as surgical operation, radiation therapy and chemotherapy, there is still a great need for improved anticancer therapeutics. Among these therapies, chemotherapy is one of the main areas for cancer treatment. Most drugs show their effect by inhibiting DNA from expressing their cytotoxicity and as a result, injuring tumor cells. However, chemotherapy lacks selectivity and consequently, does not sufficiently differentiate between tumor cells and normal cells, and therefore, adverse reactions expressed in normal cells have limited their use in therapy. Up to now, no satisfactory drugs are believed to have been discovered, and thus, an anticancer drug with reduced toxicity, better tolerability and a high therapeutic effect is very much desired.
Differentiation-inducing, antiproliferative agents among anticancer drugs are intended to induce differentiation of tumor cells for controlling their infinite proliferation and survival, rather than directly killing the cells. These agents are inferior to the anticancer drugs that directly kill tumor cells, during the formation of a tumor, but have reduced toxicity and different selectivity, and exert additive effects in combination with other antitumor therapeutics or treatments.
EP-A 0 847 992 describes monoacylated o-phenylendiamine derivatives as cell differentiation inducers. The same type of compounds is also the subject of EP-A 0 242 851. The compounds described in these applications are almost exclusively o-phenylene derivatives monoacylated with derivatives of benzoic acid. However, there is still a need to provide compounds with improved properties such as increased tolerability, less toxicity and less side effects.
Monoacylated o-phenylendiamines are known in the art as precursors for the preparation of the corresponding benzimidazoles, such preparation methods are described in DE-A 2 062 265; FR 2 167 954; Rastogi, R., and Sharma, S., Indian J. Chem., Sect. B, 21B (5) (1982) 485-487; Moll, R., et al., Z. Chem. 17 (1977) 133-134; and Hassan, H., et al., Indian J. Chem. 39B (2000) 764-768.
A preferred embodiment of this invention provides compounds which exhibit differentiation-inducing and antiproliferative effects and therefore are useful as pharmaceutical agents for treatment of malignant tumors, autoimmune diseases, dermatologic diseases and diseases caused by parasites.
This invention relates to new mono-N-acylated o-diamino substituted aromatic or heteroaromatic six membered ring systems and its pharmaceutically acceptable salt, which inhibit cell-proliferation activity and are therefore useful for the treatment of diseases such as cancer in humans or animals. This invention also relates to processes for the manufacturing of these o-diamine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of drugs for the treatment of diseases like cancer.